Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies against a wide spectrum of self-antigens, especially from the cell nucleus. Genetic predisposition is an important contributor to susceptibility to SLE in both humans and animals. Genes in multiple pathways participate in mediating disease pathogenesis, and epistatic interactions amongst these genes influence the severity of disease. One group includes genes whose products are active in physiologic pathways of waste disposal mechanisms in the body, and includes genes involved in removal of circulating immune complexes and apoptotic cells by the mononuclear phagocyte system. The second group encodes genes that regulate thresholds for tolerance and activation of T and B lymphocytes. This project is part of an interactive PPG, which seeks to address the overall hypothesis that mutations in one or more of the seven SLAM-family genes affect pathways that contribute to tolerance to selfantigens in humans and mice. Collectively, our observations made in humans and mice strongly support this Specifically we will: Aim 1. test the hypothesis that the SLAM-Family-locus {CD244<->Ly108} governs CD4 T cell and antigen presenting cell functions in the C57BL/6 mouse. Aim 2.test the hypothesis that deletion of the {CD244<->Ly108} genomic interval causes loss of tolerance toward chromatin in C57BL/6 mice. Aim 3.test the hypothesis that SLAM-family genes derived from 129Sv mice contribute to the development of lupus upon introduction into the {CD244<->Ly108}-/- C57BL/6 mouse. Together these experiments should clarify the interplay between APC, T and B cells governed by the SLAM-Family genes and their control of susceptibility to murine lupus. The results of these studies should suggest therapeutic strategies that can be applied to SLE patients.